Synthesis of new hybrid pyridines catalyzed by Fe3O4@SiO2@urea-riched ligand/Ch-Cl

Herein, a new heterogeneous catalytic system through modification of urea functionalized magnetic nanoparticles with choline chloride [Fe3O4@SiO2@urea-riched ligand/Ch-Cl] was designed and synthesized. Then, the synthesized Fe3O4@SiO2@urea-riched ligand/Ch-Cl was characterized by using FT-IR spectroscopy, FESEM, TEM, EDS-Mapping, TGA/DTG and VSM techniques. After that, the catalytic usage of Fe3O4@SiO2@urea-riched ligand/Ch-Cl was investigated for the synthesis of hybrid pyridines with sulfonate and/or indole moieties. Delightfully, the outcome was satisfactory and the applied strategy represents several advantages such as short reaction times, convenience of operation and relatively good yields of obtained products. Moreover, the catalytic behavior of several formal homogeneous DESs was investigated for the synthesis of target product. In addition, a cooperative vinylogous anomeric-based oxidation pathway was suggested as rational mechanism for the synthesis of new hybrid pyridines.


Results and discussion
A literature survey shows that in heterocyclic chemistry as a significant category of organic chemistry, pyridine plays as same as benzene in the concept of aromaticity. On the other hand, hybrid pyridines are the most heterocycle molecules which have been used for various purposes such as medicinal drugs, agricultural adducts, dyes, polymers etc. [85][86][87][88] . Therefore, development of hybrid pyridines is one of our main research interests. With this aim, herein we wish to report a new catalytic system for preparation of new hybrid pyridines with aryl, indole and sulfonate moieties.
After synthesis of Fe 3 O 4 @SiO 2 @urea-riched ligand/Ch-Cl, we focused on the precise characterization of its structure. Firstly, FT-IR spectrum of catalyst were investigated (Fig. 5). According to FT-IR spectrum of Fe 3 O 4 @ SiO 2 @urea-riched ligand/Ch-Cl, the clear peak of C=O is appeared at 1665 cm − (Fig. 6), catalyst has a spherical and uniform shapes and its size is in the range of nanometers. Also, TEM analysis was investigated to confirm the formation of the catalyst with spherical morphology and the presence of organic layers on the surface of magnetic nanoparticles is well confirmed (Fig. 7).
Energy-dispersive X-ray spectroscopy (EDS) analysis was used for the examination of expected elements within the catalyst structure. As predicted, the elements of C, N, O, Fe, Cl and Si are presented in the structure of desired catalyst (Fig. 8). In addition, elemental mapping analysis shows how the elements are dispersed and confirmed the existence of abovementioned expected elements in the structure of catalyst (Fig. 9).
For investigation of magnetic properties of target catalyst, VSM technique was performed for Fe 3 O 4 @SiO 2 @ urea-riched ligand/Ch-Cl. According to revealed results, the saturation magnetization of Fe 3 O 4 @SiO 2 @ureariched ligand/Ch-Cl is about 27 emu/g which is enough for the easy separation of the catalyst from the reaction mixture (Fig. 10).
Thermal stability is another important factor for MDES systems. Therefore, we investigated the thermal stability of the catalyst by using TGA/DTG analysis (Fig. 11). When the catalyst is exposed to the thermal conditions up to 600 °C, two main weight losses are observed at temperatures 255 and 443 °C. The poor weight losses below 110 °C is related to removing of trapped solvents and the significant weight losses at 255 °C is related to   www.nature.com/scientificreports/ decomposition of organic layers. Therefore, it can be said that the catalyst is thermally stable up to this temperature. In an overview, the decrease in the weight of the catalyst by 30.59% indicates the presence of a significant amount of organic ligand on the Fe 3 O 4 surface. At the outset of the synthesis of hybrid pyridines, benzaldehyde, 4-acetylphenyl 4-methylbenzenesulfonate, malononitrile and ammonium format were chosen as model substrates for multi-component synthesis of pyridine derivatives. At the first, the reaction conducted in the presence of different amounts of catalyst such as 5, 10 and 20 mg. Also, the model reaction was tested in the absence of any catalyst. Anyway, the best result was obtained by using 10 mg of catalyst. Subsequent study on the effect of the temperature parameter displayed that 110 °C is the most suitable temperature to provide activation energy for the model reaction. After that, for the investigation of solvent effect, the model reaction was performed in several formal polar and nonpolar solvents and also, solvent free conditions. Nonetheless, due to high yield and low toxicity of reaction and simplicity of work up, solvent free conditions were chosen as proper conditions. More details are given in the Table 1. The bold values indicates the optimal reaction conditions.
In a separate study, the model reaction was performed in the presence of formal homogeneous DESs. For this purpose, several selected homogeneous DESs was prepared [89][90][91][92][93][94] and were used as catalyst for the model reaction. Distinguishingly, these materials have a good response to the synthesis of target molecule and all of products have a relatively good yield (Table 2). Nevertheless, devoid of suitable recycling and reusing of the catalyst in homogeneous systems is one of the defecting of these systems, while Fe 3 O 4 @SiO 2 @urea-riched ligand/Ch-Cl as heterogeneous catalyst can easily recycled and reused.
For the validation of the importance of target catalyst, the model reaction was also performed in the presence of relative intermediates of Fe 3 O 4 @SiO 2 @urea-riched ligand/Ch-Cl and some of formal catalysts such as Lewis acids, protic acids, hydrogen bond and basic catalysts. Using Fe 3 O 4 @SiO 2 @urea-riched ligand/Ch-Cl as catalyst gave the best yield. It goes without saying that using of urea, thiourea and K 2 CO 3 as catalyst have relatively good yield. Nevertheless, these catalysts do not have the ability to recycle and reuse, which are the basic capabilities of a complete catalyst. (Table 3).
In a comparative and precise study, for the investigation of the ability of ammonium format as reagent, we used several ammonium sources including ammonium format, ammonium acetate, ammonium sulfate, ammonium carbonate, ammonium florid, ammonium dichromate, ammonium chloride and ammonium nitrate upon model reaction. According to revealed results (Table 4), ammonium format revealed better performance for the synthesis of 1a molecule.
Based on the in-hand results of optimization reactions, the generality of the reaction for synthesis of various hybrid pyridines was investigated. For this purpose, variety of aromatic aldehydes with electron-poor or electron-rich aryl groups, three different methyl ketones bearing indole or sulfonate groups and malononitrile or 3-(1H-indol-3-yl)-3-oxopropanenitrile were applied for the synthesis of hybrid pyridine derivatives. The   www.nature.com/scientificreports/ tolerance of the reaction to diverse starting materials displayed the broad application scope of the present route in the synthesis of complex hybrid pyridines (Table 5). Based on our knowledge from the synthesis of hybrid pyridine rings, we suggested a plausible mechanism for the synthesis of 2c (Fig. 12). At the first step, the carbonyl functional group of 4-acetylphenyl 4-methylbenzenesulfonate is activated with catalyst and reacted with ammonia (arisen from thermal dissociation of ammonium format) and via a tautomerization process gives intermediate A. In another part of the reaction, aldehyde was activated by the catalyst and by a condensation reaction with 3- (    www.nature.com/scientificreports/ Magnetic substrates serve as ideal systems in recoverable catalysts and investigation of recycling and reusing potential of nanomagnetic catalyst is very important. Therefore, we examined the recycling and reusing ability of Fe 3 O 4 @SiO 2 @urea-riched ligand/Ch-Cl for the synthesis of 1a which leads to acceptable results. After running and performing each of reactions, the mixture of reaction was dissolved in CH 2 Cl 2 and insoluble catalyst was separated from the reaction mixture and washed with CH 2 Cl 2 (3 × 10 mL) and air dried. This work was conducted five times without significant reduction in yield of the reaction (Fig. 13). In addition, FT-IR spectrum was used for investigation the stability of recovered catalyst (See ESI).  www.nature.com/scientificreports/    [70][71][72][73][74][75][76] . Then, in a 100 mL round-bottomed flask 1 g of Fe 3 O 4 @SiO 2 @urea-riched ligand and choline chloride (6 mmol, 0.837 g) and 100 mL of toluene as solvent were added and was refluxed for 24 h. After completing of reaction, the desired catalyst was separated by using external magnet and washed with n-hexane and EtOH several times and dried in air condition.
General experimental route for the synthesis of hybrid pyridine derivatives. In 10 mL roundbottomed flask methyl ketones (1 mmol), aromatic aldehydes (1 mmol), malononitrile (1 mmol, 0.066 g) or 3-(1H-indol-3-yl)-3-oxopropanenitrile (1 mmol, 0.184 g), ammonium format (1.5 mmol, 0.094 g) and 10 mg of catalyst were added and the mixture of reaction was stirred at 110 °C for appropriate times as indicated in Table 2. The progress of reactions was monitored by TLC techniques (n-hexane/ethylacetate, 6/4). After com- www.nature.com/scientificreports/ pleting of each reaction, the mixture of reaction was dissolved in CH 2 Cl 2 and the catalyst was separated from organic mixture. Then, each of products was purified by TLC plate techniques with n-hexane/ethyl acetate.

Conclusion
In summary, we reported the design, synthesis and characterization of a new heterogeneous catalytic system namely [Fe 3 O 4 @SiO 2 @urea-riched ligand/Ch-Cl]. The revealed results from characterization of this compound such as FT-IR, FESEM, TEM, EDS-Mapping, TGA/DTG and VSM analysis show its successful synthesis. This system has an excellent catalytical potential for synthesis of hybrid pyridines containing sulfonate or indole sections. In this method several starting materials were used for the synthesis of hybrid pyridine rings which yield divers products in mild reaction conditions. Besides, cooperative vinylogous anomeric-based oxidation pathway was suggested as a rational mechanism for the synthesis of hybrid pyridine (Supplementary Information S1).

Data availability
All data generated or analyzed during this study are included in this published article [and its supplementary information files].